Michael Schwameis

Intercell, Wien, Vienna, Austria

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Publications (10)35.68 Total impact

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    ABSTRACT: Introduction IC43 is a recombinant outer membrane protein-based vaccine against Pseudomonas aeruginosa (P. aeruginosa) consisting of OprF- and OprI- epitopes (Opr, outer membrane protein; OprF/I, OprF/OprI hybrid vaccine) with an N-terminal His 6 tag (Met-Ala-(His)6-OprF 190-342-OprI 21-83). Objectives The study aimed to confirm the optimal dose of IC43 in adults with regard to immunogenicity, safety, and tolerability after vaccination with three different dosages of IC43, compared with placebo, and to investigate a potential immune-enhancing effect of the adjuvant, aluminum hydroxide. Subjects were randomly allocated in a 1:1:1:1:1 ratio to one of five treatment groups: 50, 100, or 200 µg IC43 with adjuvant, 100 µg IC43 without adjuvant, or placebo (0.9% sodium chloride) and two intramuscular injections were given in the deltoid region 7 d apart. Results The primary immunogenicity analysis of OprF/I-specific IgG antibody titers on day 14 demonstrated statistically significant differences among treatment groups (P<0.0001), with a significantly higher immune response detected in each IC43 treatment group compared with placebo. From day 0 to day 14, a ≥ 4-fold increase in OprF/I-specific immuneglobulin G (IgG) antibody titers were observed in>90% of subjects in all IC43 treatment groups in the per-protocol (PP) and intention-to-treat (ITT) populations; a ≥ 50-fold titer increase was observed in 42.6% subjects including all IC43 treatment groups. On day 90, OprF/I-specific IgGs started to decline in all IC43 treatment groups but remained significantly higher until 6 mo compared with placebo. Assessment of functional antibody induction by opsonophagocytic assay (OPA) followed a similar pattern compared with OprF/I-specific IgG kinetics. At day 14, a ≥ 2-fold increase in OPA titer was observed in 54.5% subjects within all IC43 treatment groups. An increase in antibody avidity index was observed after the second vaccination. At day 14,>96% of subjects in each IC43 treatment group had detectable OprF/I-specific IgG antibodies. Anti-histidine IgG antibody titers peaked on day 14 and were reduced on day 90 in all IC43 treatment groups. OprF/I-specific IgG secreted by antibody-secreting cell (ASC) was detected in all IC43 groups by B-cell ELIspot after the second vaccination and up to 6 mo. All vaccinations were safe and well tolerated up to the maximum cumulative dosage of 400 µg IC43. Conclusion IC43 doses equal to or greater than 50 µg were sufficient to induce a plateau of IgG antibody responses in healthy volunteers. Higher doses, whether adjuvanted or non-adjuvanted, were not more effective. Methods In this phase I, randomized, placebo-controlled, observer-blinded, multicenter clinical trial, 163 healthy volunteers (18-65 y) were randomly assigned to five treatment groups (1:1:1:1:1). Three groups received IC43 with adjuvant: 50 µg (n = 32), 100 µg (n = 33), or 200 µg (n = 33). One group received IC43 100 µg without adjuvant (n = 32), and one group received placebo (0.9% sodium chloride) (n = 33). Each subject received two intramuscular vaccinations, separated by a 7-d interval (days 0 and 7) (Fig. 1). Humoral immune response was assessed by measurement of outer membrane protein F/I (OprF/I)-specific antibodies determined by enzyme-linked immunosorbent assay (ELISA), anti-histidine antibodies determined by ELISA, and functional antibody activity determined by opsonophagocytic assay (OPA), up to 6 mo post-vaccination. Antibody avidity was measured on days 7 and 14 from samples that had detectable vaccine antibody-specific immunoglobulin G (IgG) antibody titers. At the Austrian site only, the B-cell ELIspot assay was used to determine specific ASC responses. Safety was assessed using adverse event monitoring and clinical laboratory tests. Local and systemic tolerability was recorded in a subject diary for 7 d after each vaccination and by investigators up to 6 mo post-vaccination.
    Human vaccines & immunotherapeutics. 09/2013; 10(1).
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    ABSTRACT: Patients on antiplatelet therapy have a higher incidence of bleeding complications. Reversal of antiplatelet drug effects is an important issue at trauma or emergency departments. For old and conventional anticoagulants, reversal strategies are established. While the effects of ticagrelor are reversible, developing a method to restore platelet function in patients is of importance due to its longer half-life (approximately 8 h), compared with other P2Y12 -inhibitors. We report an ex vivo model to reverse the effects of the novel and highly effective P2Y12 -inhibitor ticagrelor in 20 healthy volunteers. To normalize platelet reactivity, we added increasing amounts of autologous platelet-rich plasma (PRP) to whole blood which was obtained 3 h after the intake of 180 mg of ticagrelor. Platelet aggregation was assessed by whole blood multiple electrode aggregometry (MEA), which is based on impedance aggregometry. The basal ADP-induced platelet aggregation averaged 71 ± 16 U (Units). Ticagrelor decreased ADP-induced platelet aggregation to 16 ± 8 U. A clear dose-response was obtained after spiking whole blood with increasing amounts of PRP. It is estimated that ≥2 units of apheresis platelet concentrates will be necessary to completely restore baseline platelet aggregation in the majority of patients after ticagrelor. Platelets dose dependently improve ex vivo platelet aggregation of subjects after a loading dose of 180 mg of ticagrelor, making transfusion of platelet concentrates potentially useful in bleeding patients and those who need to undergo emergency surgery.
    European Journal of Clinical Investigation 08/2013; · 3.37 Impact Factor
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    ABSTRACT: Erythropoiesis stimulating agents (ESAs) are used to treat anemia in critically ill patients. This indication is off-label, because it is not licensed by regulatory authorities. Recently ESAs were suspected to harm critically ill patients. Our objective was to assess the safety of ESAs in off-label indications in critically ill patients. Eleven databases were searched up to April 2012. We considered randomized controlled trials (RCTs) and controlled observational studies in any language that compared off-label ESAs treatment with other effective interventions, placebo or no treatment in critically ill patients. Two authors independently screened and evaluated retrieved records, extracted data and assessed risk of bias and quality of reporting. We used frequentist and Bayesian models to combine studies, and performed sensitivity and subgroup analyses. From 12,888 citations, we included 48 studies (34 RCTs; 14 observational), involving 944,856 participants. Harm reporting was of medium to low quality. There was no statistically significant increased risk of adverse events in general, serious adverse events, the most frequently reported adverse events, and death in critically ill patients treated with ESAs. These results were robust against risk of bias and analysis methods. There is evidence that ESAs increase the risk of clinically relevant thrombotic vascular events, and there is some less certain evidence that ESAs might increase the risk for venous thromboembolism. In critically ill patients, administration of ESAs is associated with a significant increase in clinically relevant thrombotic vascular events but not with other frequently reported adverse events and death.
    European Journal of Intensive Care Medicine 08/2013; · 5.17 Impact Factor
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    ABSTRACT: Ticagrelor is a P2Y12 receptor antagonist, with superior effects but also ensuing enhanced bleeding risk as compared to clopidogrel. Determination of platelet inhibition may be useful to confirm efficient platelet inhibition on an individual patient level and to identify patients at risk for bleeding. The vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation assay specifically measures platelet P2Y12 inhibition, but has so far required individual sample processing. A new ELISA-based VASP assay has been developed which allows batch analysis after initial platelet activation. Due to the reversible binding of ticagrelor it is unclear if the ELISA and flow cytometric assays provide comparable results; several washing steps of the ELISA may potentially result in false low results through dilution. We hypothesized that the conventional and new methods may be comparable when ticagrelor is used. We pair-wise compared the platelet reactivity index (PRI) between assays in a prospective clinical trial. Six healthy volunteers received a single 180 mg loading dose of ticagrelor. PRI-values of the two methods correlated well (r=0.97, p<0.001). Ticagrelor rapidly decreased PRI values on average after 50 minutes, but nadir levels 2-6 hours after ticagrelor intake were 15% higher when PRI% was measured with the flow cytometric method. Bland-Altman analysis showed that the flow cytometric assay measured markedly higher PRI levels than the new ELISA-based technique (mean difference 13%). The new ELISA-based VASP assay offers an alternative to the currently used flow cytometric method, but measures lower PRI levels, particularly when PRI falls below 20% after ticagrelor intake. © 2013 Clinical Cytometry Society.
    Cytometry Part B Clinical Cytometry 07/2013; · 2.23 Impact Factor
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    ABSTRACT: BACKGROUND: Octaplas LG is a prion-depleted version of a previous generation product called Octaplas S/D. We compared the recovery, safety, and tolerability of these two pharmaceutical-grade plasmas. STUDY DESIGN AND METHODS: In this comparative, block-randomized, open-label, active-controlled, crossover Phase I trial, 60 healthy adult volunteers received single transfusions of 1200 mL of parent product (in Period 1) and of the LG plasma product (in Period 2) or vice versa. In both periods, plasmapheresis (600 mL) preceded the transfusion. Blood samples were drawn before and after apheresis and 15 minutes, 2 hours, 24 hours, and 7 days after end of plasma transfusion, to assess recovery, safety, and tolerability. The primary efficacy endpoints were the changes in coagulation factors and hemostatic variables compared to baseline; their relative recovery was computed in the per-protocol analysis (n = 43). Safety and tolerability were assessed (n = 60). RESULTS: Variations in coagulation factors and hemostatic variables over time were similar between the two treatments and within normal range; 90% confidence intervals for the derived recovery data were within predefined limits of equivalence. Both products were well tolerated. The advanced manufacturing process also significantly increased plasmin inhibitor concentrations after transfusion in vivo. CONCLUSION: The LG plasma product was bioequivalent to its predecessor with respect to recovery of clotting factors and demonstrated comparable safety and tolerability in healthy volunteers. Both products compensated well for the loss of clotting factors after apheresis (NCT01063595).
    Transfusion 01/2013; · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Carotid duplex ultrasonography is the prime investigation used to grade carotid artery stenosis in clinical routine. We compared the carotid ultrasound (US) scans performed externally with our results. MATERIALS AND METHODS: This retrospective study included 288 patients who had been referred to our outpatient department and initially presented with an external carotid duplex scan report indicating carotid atherosclerosis. The external scans were analyzed and compared with our scans in respect of the accuracy of identification and quantification of stenosis, the criteria used to grade stenosis and the duplex criteria used. Weighted Kappa coefficients (K) were computed to quantify the agreement between internal and external findings. RESULTS: The majority of the external reports had been performed by radiologists [70.8 % (n = 204)], followed by specialists of internal medicine [19.4 (n = 56)] and by neurologists [9.8 % (n = 28)]. Only slight agreement was registered between the external reports and those performed at our institution with regard to the identification of stenosis (K = 0.2 for the left and K = 0.12 for the right side). Greater agreement was observed in respect of the level of stenosis (K = 0.42 for the right and K = 0.54 for the left side). Overestimation of the level of stenosis was registered for 45 % in the left internal carotid artery (ICA) and 36 % in the right ICA; the overestimation was most pronounced for occlusions and high-grade stenoses, which is a source of great concern for decision-making. CONCLUSIONS: The present data indicate only a slight agreement between carotid duplex US imaging performed at medical offices and our results.
    Wiener klinische Wochenschrift 11/2012; · 0.81 Impact Factor
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    ABSTRACT: P2Y(12) receptor antagonists have become a mainstay for the treatment of CVD (cardiovascular diseases). However, they have rarely been evaluated under pathophysiological conditions apart from arterial diseases. We hypothesized interactions between prasugrel and enhanced vWF (von Willebrand Factor) release in a model of systemic inflammation, and compared the pharmacodynamic effects of prasugrel against placebo on agonist-induced platelet aggregation and shear-induced platelet plug formation. A total of 20 healthy male volunteers were enrolled in a double-blind placebo-controlled two-way crossover trial. Each volunteer received either placebo or a 60 mg loading dose of prasugrel 2 h before endotoxin or placebo infusion. Platelet inhibition was measured with MEA (multiple electrode aggregometry), the PFA-100 system and the VASP (vasodilator-stimulated phosphoprotein) phosphorylation assay. Prasugrel blunted various platelet aggregation pathways, including those induced by ADP (-81%), AA (arachidonic acid) (-60%), ristocetin (-75%; P<0.001 for all) and, to a lesser degree, collagen or TRAP (thrombin-receptor-activating peptide). Prasugrel decreased shear-induced platelet plug formation, but vWF release during endotoxaemia partly antagonized the inhibitory effect of prasugrel as measured with the PFA-100 system. Endotoxaemia acutely decreased ristocetin and TRAP-induced platelet aggregation, and enhanced ristocetin-induced aggregation after 24 h. Strong in vivo blockade of P2Y(12) inhibits a broad spectrum of platelet aggregation pathways. However, vWF release may reduce prasugrel's effects under high-shear conditions.
    Clinical Science 05/2012; 123(10):591-600. · 4.86 Impact Factor
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    ABSTRACT: Thrombin is the central protease in the coagulation cascade and one of the most extensively studied of all enzymes. In addition to its recognised role in the coagulation cascade and haemostasis, thrombin is known to have multiple pleiotropic effects, which mostly have been shown only in in vitro studies: it plays a role in inflammation and cellular proliferation and displays a mitogen activity on smooth muscle cells and endothelial cells, predominantly by activation of angiogenesis. In vivo , thrombin effects were examined in animal models of intravenous or intraarterial thrombin infusion. An extensive literature search regarding in vivo data showed that i) thrombin administered as a bolus causes microembolism, ii) thrombin infused slowly at steady-state conditions (up to 1.6 U/kg/min) leads to bleeds but not to intravascular clotting, iii) large quantity of thrombin infused at low rates (0.05 U/kg/min) does not have any measurable effect, and iv) thrombin increases vascular permeability leading to tissue damage. Although several decades of research on thrombin functions have provided a framework for understanding the biology of thrombin, animal and human studies with use of newer laboratory techniques are still needed to confirm the pleiotropic thrombin functions shown in in vitro studies.
    Thrombosis and Haemostasis 12/2011; 106(6):1020-33. · 6.09 Impact Factor
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    ABSTRACT: Universal plasma is intended to be transfused irrespective of the blood group. We compared the safety and tolerability of a novel, universal blood group-independent plasma with an ABO-matched plasma. In this randomized, double-blind, active-controlled, crossover, Phase I trial, 30 healthy adult volunteers (blood group A, B, or AB) were randomly assigned to transfusion of 1200 mL of Uniplas LG and 1200 mL of Octaplas LG (both Octapharma AG) or vice versa. In both periods, plasmapheresis (PPh, 600 mL) preceded the infusion. Blood samples were drawn before and after PPh and 15 minutes, 2 hours, 24 hours, and 7 days after end of plasma transfusion, to assess safety and efficacy. The primary safety outcome was change in hemoglobin (Hb) concentration; secondary safety outcomes were direct antiglobulin test (DAT), complement activation, free Hb, haptoglobin, and indirect bilirubin. Efficacy was assessed by evaluation of coagulation variables. Variations of Hb concentration were similar between treatments and within normal range; 90% confidence interval was within predefined limits of equivalence. No subject exhibited a positive DAT. All other secondary variables which could reflect hemolytic transfusion reactions (HTRs) fell within normal range; this suggests that no HTRs occurred. Most adverse events were of mild intensity; two subjects experienced dyspnea, leading to the withdrawal from the study of one subject. Universal plasma was equivalent to ABO-matched plasma with respect to safety and tolerability. Eliminating the risk of ABO incompatibility, this universal plasma represents an advance over blood group-specific plasma.
    Transfusion 02/2011; 51(6):1228-40. · 3.53 Impact Factor
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    ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) stimulates the bone marrow to produce granulocytes and stem cells and is widely used to accelerate neutrophil recovery after chemotherapy. Interestingly, specific G-CSF receptors have been demonstrated not only on myeloid cells, but also on platelets. Data on the effects of G-CSF on platelet function are limited and partly conflicting. The objective of this study was to determine the effect of G-CSF on platelet aggregation and in vivo platelet activation. Seventy-eight, healthy volunteers were enrolled into this randomised, placebo-controlled trial. Subjects received 5 μg/kg methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) or placebo subcutaneously for four days. We determined platelet aggregation with a whole blood impedance aggregometer with various, clinically relevant platelet agonists (adenosine diphosphate [ADP], collagen, arachidonic acid [AA], ristocetin and thrombin receptor activating peptide 6 [TRAP]). Filgrastim injection significantly enhanced ADP (+40%), collagen (+60%) and AA (+75%)-induced platelet aggregation (all p<0.01 as compared to placebo and p<0.001 as compared to baseline). In addition, G-CSF enhanced ristocetin-induced platelet aggregation (+18%) whereas TRAP-induced platelet aggregation decreased slightly (-14%) in response to filgrastim. While baseline aggregation with all agonists was only slightly but insignificantly higher in women than in men, this sex difference was enhanced by G-CSF treatment, and became most pronounced for ADP after five days (p<0.001). Enhanced platelet aggregation translated into a 75% increase in platelet activation as measured by circulating soluble P-selectin. G-CSF enhances platelet aggregation and activation in humans. This may put patients suffering from cardiovascular disease and cancer at risk for thrombotic events.
    Thrombosis and Haemostasis 02/2011; 105(4):655-62. · 6.09 Impact Factor